By David N. Leff

Crop-dusting airplanes are in the news these days as putative delivery vehicles for spraying biowarfare organisms ¿ anthrax for example ¿ on helpless cities.

Such a devilish contrivance already exists ¿ thanks to Mother Nature. Its winged perpetrator is the Anopheles mosquito; its fiendishly lethal payload, the malarial parasite, Plasmodium falciparum.

This immeasurably efficient bioweapon has defeated every defense mechanism deployed by hapless Homo sapiens in the last half-century. When DDT (dichloro-diphenyl-trichloroethane) was introduced late in World War II, this all-purpose, potent insecticide was hailed as portending the death of Anopheles. Reports of that death proved greatly exaggerated. Because of its devastating effect on innocent bystander forms of life, DDT was soon banned from the environment.

Then one by one, the proliferation of chemotherapeutic compounds, targeted at malarial infections, fell by the wayside ¿ shrugged off by drug-resistant malarial parasites. A succession of promising vaccines against the infection have failed to keep their promise. So malaria takes the lives of some 2 million people a year in Africa alone, most of them children.

One of the earliest pioneers of malarial vaccine development is immuno-malariologist Ruth Nussenzweig, who holds an endowed chair of medical and molecular parasitology at New York University School of Medicine (NYU). She discerns three keys to making prototype vaccines fulfill their promise ¿ timing, timing, timing.

Nussenzweig puts her data where her theory is, in a paper of which she is senior author, released electronically Sept. 11, 2001, by the Proceedings of the National Academy of Sciences (PNAS). Its title: ¿Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen.¿

¿The important finding of this paper,¿ Nussenzweig told BioWorld Today, ¿was that in general vaccines against malaria have short duration. That means their protection against infection persists for only a little time. In fact, I have a paper here from the Army, which did a field trial in the U.S., and after a few months the immunity was gone. And they found the same thing in Gambia, where they immunized with the same antigen that was protective in malaria-naove people in the U.S. and in Europe, but only when they used a certain combination of several adjuvants. And in Gambia they apparently used a somewhat modified mix of adjuvants, where they immunized not very large numbers ¿ a few hundred adults.¿

Army Field-Tests Malaria Vaccine In Gambia

The tiny West African country of Gambia is where the largest number of lethal cerebral malaria infections occur in kids. Hence, it¿s a test bed for experimental vaccines.

¿Gambia usually has high malaria transmission for only three months of the year ¿ November, December, January,¿ Nussenzweig observed. ¿Most of the malaria infections occur soon after that ¿ unless there¿s a dry season. In the U.S.,¿ she continued, ¿they had to challenge their vaccinated mice with laboratory-bred infected mosquitoes. But in Gambia, they just looked in the immunized control group, and scored about 60 percent protection in the immunized group. Then when they looked again six months later, it was only 20 percent. So it¿s the old story we also see in mice: Whatever you do, there may be 100 percent protection to start with, but then after a relatively short time, they are no longer protected.

¿So here in this PNAS paper,¿ she went on, ¿we show that even after 3.5 months you still have protection. For a mouse, which normally lives one year or a bit more, that is quite an advanced age. And it is much more than had been obtained before.

¿The vaccine was only like that,¿ Nussenzweig pointed out, ¿because we boosted it. We found out when the response to the priming antigen was gone, which was exactly at eight weeks. So then we decided to boost. We did so at two weeks, four weeks, 12 weeks ¿ whatever. But our best result was obtained at eight weeks, when the primary immune response had already practically disappeared. We found that there were no longer any CD8 T cells left from the primary immune response.

¿The explanation,¿ Nussenzweig surmised, ¿is that maybe, as with antibodies, when you have a lot of antibodies, and then boost, it doesn¿t help, because it makes immune complexes, which deposit in various tissues. So this is a new concept ¿ in relation to T cells ¿ that we had to find out: When priming with a given antigen is low, practically zero, is the time to boost.¿

To test their newest vaccine in vivo, Nussenzweig recounted, ¿We used mice that were 100 percent protected when we challenged them two weeks after the booster. Ten out of 10 had no circulating blood-stage parasites. Six weeks after boosting, it was again 10 out of 10. The next one, after 10 weeks was 5 out of 6, 83 percent, and then at 16 weeks 2 out of 5 ¿ 40 percent protected. So it went down with time; this was complete protection of the mice ¿ sterile immunity.¿

New Gig For Adenovirus Vectors

¿The vaccine with which we immunized them,¿ she continued, ¿consisted of two recombinant adenovirus vectors [AV] ¿ much used in experimental gene therapy. You couldn¿t possibly inject the AV vector into people, because there are lots of Americans who already have antibody against it. We didn¿t want any protection from AV so we diluted the viruses 10-fold. They carried practically the whole circumsporozoite parasite protein, as the vaccine¿s target antigen. The viral vectors had the advantage that they protect without any adjuvants.

¿In our in vivo experiments,¿ she narrated, ¿we infected the mice with Plasmodium yoelii, the rodent equivalent of P. falciparum in humans. It¿s a good model for human vaccines against the sporozoite¿s liver stage.¿

Nussenzweig is now developing a new vaccine that ¿will be tried in humans early next year. It will have two recombinant viral vectors, which express the circumsporite protein, that are safe for human use.

¿We¿d like to come up with some investor who might be interested in funding our work,¿ she added. ¿It wouldn¿t have to be millions, but it would have to be pretty soon. It¿s very, very difficult developing malaria vaccines,¿ Nussenzweig concluded, ¿in a budget-limited academic setting.¿

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